Mutations that occur spontaneously in mice provide valuable models for human inherited disorders and contribute to our understanding of basic biological processes important to biomedical research. The MMR at The Jackson Laboratory has a long-standing program for discovering and analyzing new spontaneous mouse mutations. The new molecular and genetic analyses proposed in this grant application could increase the scope and extend the depth of analysis of new mouse mutations discovered and maintained in the MMR. One of the objectives of this research project is to improve the precision and efficiency of genetic mapping methods so that more genetically well-characterized new mutations will be made available to the research community. The accurate mapping of mouse mutations is important because it helps identify the molecular basis of mutant phenotypes. In addition, because of the many conserved gene arrangements that have been identified between the mouse and human genomes, knowing the map location of a mouse mutation can help identify the equivalent human genetic disease. A specific aim of this research project is to characterize a large number of multigene families so that they can be used as genomic reference markers to efficiently map the many new mouse mutations that occur among the large colonies of mice maintained at The Jackson Laboratory. Precise chromosomal localizations of these many spontaneous mutations will inevitably identify several candidate genes that map to the same position and whose dysfunction could result in the observed mutant phenotypes. Another goal of this project is to test such candidate genes for genetic recombination with the newly mapped mutations and perform initial examinations for DNA and mRNA differences between mutant and control mice. The multilocus probe mapping methodology developed to map new mutations will also be used to map modifier genes that alter the phenotypic expression of particular mutations. Identification of modifier genes and their effects on mutant phenotypes would aid in the understanding of mammalian gene interactions. Finally, new molecular techniques will be applied to other aspects of the MMR program for maintaining and analyzing mouse mutations.